METHOTREXATE- methotrexate_injection, solution

Methotrexate inhibits dihydrofolic acid reductase. Dihydrofolates must be reduced to tetrahydrofolates by this enzyme before they can be utilized as carriers of one-carbon groups in the synthesis of purine nucleotides and thymidylate. Therefore, methotrexate interferes with DNA synthesis, repair, and cellular replication. Actively proliferating tissues such as malignant cells, bone marrow, fetal cells, buccal and intestinal mucosa, and cells of the urinary bladder are in general more sensitive to this effect of methotrexate. The mechanism of action in rheumatoid arthritis, pJIA, and in psoriasis is unknown. Distribution After intravenous administration, the initial volume of distribution is approximately 0. 18 L/kg (18% of body weight) and steady-state volume of distribution is approximately 0. 8 L/kg (40% to 80% of body weight). Methotrexate competes with reduced folates for active transport across cell membranes by means of a single carrier-mediated active transport process. At serum concentrations greater than 100 micromolar, passive diffusion becomes a major pathway by which effective intracellular concentrations can be achieved. Methotrexate in serum is approximately 50% protein bound. Methotrexate may be displaced from plasma albumin by various compounds, including sulfonamides, salicylates, tetracyclines, chloramphenicol, and phenytoin. Methotrexate does not penetrate the blood-cerebrospinal fluid barrier in therapeutic amounts when given intravenously, intramuscularly, or subcutaneously. Elimination The terminal half-life reported for methotrexate is approximately 3 to 10 hours for patients receiving treatment for psoriasis, or rheumatoid arthritis or low-dose antineoplastic therapy (less than 30 mg/m 2 Following intravenous administration of high-dose methotrexate, the terminal half-life is 8 hours to 15 hours. Metabolism Methotrexate undergoes hepatic and intracellular metabolism to polyglutamated forms that can be converted back to methotrexate by hydrolase enzymes. These polyglutamates act as inhibitors of dihydrofolate reductase and thymidylate synthetase. Small amounts of methotrexate polyglutamates may remain in tissues for extended periods. The retention and prolonged drug action of these active metabolites vary among different cells, tissues, and tumors. Methotrexate undergoes minor metabolism to 7-hydroxymethotrexate, and accumulation may become significant following high dosages. The aqueous solubility of 7-hydroxymethotrexate is 3- to 5-fold lower than the solubility of methotrexate. Excretion Renal excretion is the primary route of elimination and is dependent upon dosage and route of administration. With intravenous administration, 80% to 90% of the administered dose is excreted unchanged in the urine within 24 hours. There is limited biliary excretion amounting to 10% or less of the administered dose. Enterohepatic recirculation of methotrexate has been proposed. Renal excretion occurs by glomerular filtration and active tubular secretion. Nonlinear elimination due to saturation of renal tubular reabsorption has been observed in psoriatic patients at doses between 7. 5 mg and 30 mg. Specific Populations Pediatric Patients In pediatric patients receiving methotrexate for acute lymphoblastic leukemia (6. 3 mg/m 2 2 2 2 [see Use in Specific Populations (8. 4) Patients with Renal impairment The elimination half-life of methotrexate increases with the severity of renal impairment, with high inter-individual variability [see Use in Specific Populations (8.

Methotrexate Injection is a folate analog metabolic inhibitor indicated for: o 1. 10 Methotrexate Injection is indicated for the treatment of adult and pediatric patients with acute lymphoblastic leukemia (ALL) as part of a combination chemotherapy regimen. Methotrexate Injection is indicated for the prophylaxis and treatment of meningeal leukemia in adult and pediatric patients. Methotrexate Injection is indicated for the treatment of adults and pediatric patients with non-Hodgkin lymphoma. Methotrexate Injection is indicated for the treatment of adults and pediatric patients with osteosarcoma as part of a combination chemotherapy regimen. Methotrexate Injection is indicated for the treatment of adults with breast cancer as part of a combination chemotherapy regimen. Methotrexate Injection is indicated for the treatment of adults with squamous cell carcinoma of the head and neck as a single agent. Methotrexate Injection is indicated for the treatment of adults with gestational trophoblastic neoplasia (GTN) as part of a combination chemotherapy regimen. Methotrexate Injection is indicated for the treatment of adults with rheumatoid arthritis (RA). Methotrexate Injection is indicated for the treatment of pediatric patients with polyarticular Juvenile Idiopathic Arthritis (pJIA). Methotrexate Injection is indicated for the treatment of adults with severe psoriasis.

10 2 2. 11 2. 12 Use only preservative-free Methotrexate Injection for treatment of neonates or low birth weight infants and for intrathecal use. Do not use benzyl alcohol-containing formulations for high-dose regimens unless immediate treatment is required and preservative-free formulations are not available [see Warnings and Precautions (5. 3) Use in Specific Populations (8. 4) [see Contraindications (4) Warnings and Precautions (5. 1) To decrease the risk of severe adverse reactions [see Warnings and Precautions (5) 2. 2 2 Refer to the leucovorin prescribing information for additional information. - - - - Methotrexate Injection is used as part of a multi-drug regimen. The recommended dosage varies from 10 to 5000 mg/m 2 [see Dosage and Administration (2. 2) 2 Use only preservative-free Methotrexate Injection for intrathecal use. Prior to administration, dilute preservative-free Methotrexate Injection to a concentration of 1 mg/mL in preservative-free 0. 9% Sodium Chloride Injection, USP. The recommended intrathecal dose of Methotrexate Injection (preservative-free) is based on age: For treatment of meningeal leukemia, intrathecal methotrexate may be given at intervals of 2 or more days up to twice weekly; however, administration at intervals of less than 1 week may result in increased subacute toxicity. For meningeal leukemia prophylaxis, Methotrexate Injection is administered no more than once weekly. For patients with Down Syndrome, administer leucovorin rescue with intrathecal Methotrexate Injection. The recommended dosage of Methotrexate Injection varies. When used in combination, recommended dosages range from 10 mg/m 2 2 2 As part of a combination chemotherapy regimen, a recommended dosage of Methotrexate Injection is 1000 mg/m 2 2 [see Dosage and Administration (2. 2) For central nervous system-directed therapy, a recommended dosage of Methotrexate Injection is 8000 mg/m 2 2 2 [see Dosage and Administration (2. 2) For intrathecal Methotrexate Injection (preservative-free), the recommended dose is based on age [see Dosage and Administration (2. 4) The recommended dosage of Methotrexate Injection is typically 12 g/m 2 [see Dosage and Administration (2. 2) A recommended dosage of Methotrexate Injection is 40 mg/m 2 The recommended dosage of Methotrexate Injection ranges from 40 to 60 mg/m 2 For patients with low-risk gestational trophoblastic neoplasia (GTN) a recommended dosage for Methotrexate Injection is 30 mg/m 2 2 For patients with high-risk GTN, a recommended dosage for Methotrexate Injection is 300 mg/m 2 The recommended starting dosage of Methotrexate Injection is 7. 5 mg once weekly, administered intramuscularly with escalation to achieve optimal response. Dosages of more than 20 mg once weekly result in an increased risk of serious adverse reactions, including myelosuppression. When responses are observed, the majority occurred between 3 and 6 weeks from initiation of treatment; however, responses have occurred up to 12 weeks after treatment initiation. Administer folic acid or folinic acid to reduce the risk of methotrexate adverse reactions [see Warnings and Precautions (5. 12) The recommended starting dosage of Methotrexate Injection is 10 mg/m 2 2 Administer folic acid or folinic acid to reduce the risk of methotrexate adverse reactions [see Warnings and Precautions (5. 12) The recommended dosage of Methotrexate Injection is 10 mg to 25 mg intramuscularly or intravenously once weekly until adequate response is achieved. Adjust the dose gradually to achieve optimal clinical response; do not exceed 25 mg per week. Once optimal clinical response has been achieved, reduce the dosage to the lowest possible dosing regimen. 12) Discontinue Methotrexate Injection for: [see Warnings and Precautions (5. 2) [see Warnings and Precautions (5. 13) Withhold, dose reduce or discontinue Methotrexate Injection as appropriate for: [see Warnings and Precautions (5. 4) Withhold or discontinue Methotrexate Injection as appropriate for: [see Warnings and Precautions (5. 5) [see Warnings and Precautions (5. 6) [see Warnings and Precautions (5. 7) [see Warnings and Precautions (5. 8) [see Warnings and Precautions (5. 9) [see Warnings and Precautions (5. 10) [see Warnings and Precautions (5. 11) Methotrexate Injection is a hazardous drug. Follow applicable special handling and disposable procedures. 1 With Preservative (Multiple-Dose Vial) [see Dosage and Administration (2. 1) Methotrexate Injection preservative-free may be administered by intramuscular, intravenous, subcutaneous, or intrathecal injection. Use only [see Warning and Precautions (5. 4) Use preservative-free Methotrexate Injection for high-dose regimens unless immediate treatment is required, and preservative-free formulations are not available [see Warning and Precautions (5. 4)] .

The following adverse reactions are described, or described in greater detail, in other sections: [see Warnings and Precautions (5. 2) [see Warnings and Precautions (5. 4) [see Warnings and Precautions (5. 5) [see Warnings and Precautions (5. 6) [see Warnings and Precautions (5. 7) [see Warnings and Precautions (5. 8) [see Warnings and Precautions (5. 9) [see Warnings and Precautions (5. 10) [see Warnings and Precautions (5. 11) [see Warnings and Precautions (5. 13) [see Warnings and Precautions (5. 14) [see Warnings and Precautions (5. 17) Common adverse reactions include ulcerative stomatitis, leukopenia, nausea, and abdominal distress. 1 To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www. gov/medwatch Because clinical trials and other studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Commonly reported adverse reactions include ulcerative stomatitis, leukopenia, nausea, and abdominal distress. Other frequently reported adverse reactions are infection, malaise, fatigue, chills, fever, and dizziness. Rheumatoid Arthritis The approximate incidences of methotrexate-attributed (i. , placebo rate subtracted) adverse reactions in 12- to 18-week double-blind studies in patients (n = 128) with RA treated with low-dose oral (7. 5 mg per week to 15 mg per week) pulse methotrexate are listed below. Most patients were on concomitant NSAIDs and some received corticosteroids. Hepatic histology was not examined in these short-term studies. Incidence >=10%: Incidence 3% to <10%: 3 Incidence 1% to <3%: 3 Two other controlled trials of patients (n = 680) with RA on 7. 5 mg per week to 15 mg per week oral doses showed the following adverse reactions: Incidence 1%: Other less common adverse reactions: Polyarticular Juvenile Idiopathic Arthritis (pJIA) The approximate incidences of adverse reactions reported in patients 2 to 18 years of age with pJIA treated with oral, weekly doses of methotrexate (5 mg/m 2 2 Psoriasis In two published series of adult psoriasis patients (n = 204, 248) treated with methotrexate doses up to 25 mg per week for up to 4 years, adverse reaction rates were similar to those in patients with RA, except for alopecia, photosensitivity, and "burning of skin lesions" (each 3% to 10%). Painful plaque erosions have been reported. The following adverse reactions have been identified during post-approval use of methotrexate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and lymphatic system disorders: Cardiovascular disorders: Endocrine: Eye disorders: Gastrointestinal disorders: Hepatobiliary disorders: Immune system disorders: Metabolism: Musculoskeletal disorders: Nervous system disorders: Renal disorders: Reproductive disorders: Respiratory disorders: Skin disorders: General disorders and administration site conditions:.

Methotrexate Injection is contraindicated in: [see Warnings and Precautions (5. 2) [see Warnings and Precautions (5. 1) Use in Specific Populations (8. 1) 4 4.

4 Risk Summary Methotrexate Injection is contraindicated in pregnant women with non-neoplastic diseases. Based on published reports and its mechanism of action, methotrexate can cause embryo-fetal toxicity and fetal death when administered to a pregnant woman [see Data Clinical Pharmacology (12. 1) [see Warnings and Precautions (5. 3) Use in Specific Populations (8. 4) In the U. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2en dash4% and 15en dash20%, respectively. Data Human Data Published data from case reports, literature reviews, and observational studies report that methotrexate exposure during pregnancy is associated with an increased risk of embryo-fetal toxicity and fetal death. Methotrexate exposure during the first trimester of pregnancy is associated with an increased incidence of spontaneous abortions and multiple adverse developmental outcomes, including skull anomalies, facial dysmorphism, CNS abnormalities, limb abnormalities, and sometimes cardiac anomalies and intellectual impairment. Adverse outcomes associated with exposure during second and third trimesters of pregnancy include intrauterine growth restriction and functional abnormalities. Because methotrexate is widely distributed and persists in the body for a prolonged period, there is a potential risk to the fetus from preconception methotrexate exposure. A prospective multicenter study evaluated pregnancy outcomes in women taking methotrexate less than or equal to 30 mg per week after conception. The rate of spontaneous abortion/miscarriage in pregnant women exposed to methotrexate was 42. 5% (95% confidence interval [95% CI] 29. 7), which was higher than in unexposed patients with autoimmune disease (22. 5%, 95% CI 16. 7) and unexposed patients with non-autoimmune disease (17. 3%, 95% CI 13en dash22. Of the live births, the rate of major birth defects in pregnant women exposed to methotrexate after conception was higher than in unexposed patients with autoimmune disease (adjusted odds ratio (OR) 1. 8 [95% CI 0. 7]) and unexposed patients with non-autoimmune disease (adjusted OR 3. 1 [95% CI 1. Major birth defects associated with pregnancies exposed to methotrexate after conception were not always consistent with methotrexate-associated adverse developmental outcomes. Risk Summary Limited published literature reports the presence of methotrexate in human milk in low amounts, with the highest breast milk to plasma concentration ration reported to be 0. No information is available on the effects of methotrexate on a breastfed infant or on milk production. Because of the potential for serious adverse reactions from methotrexate in breastfed infants, advise women not to breastfeed during treatment with Methotrexate Injection and for 1 week after the last dose. Methotrexate can cause malformations and fetal death at doses less than or equal to the recommended clinical doses [see Use in Specific Populations (8. 1) Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating Methotrexate Injection [see Contraindications (4) Use in Specific Populations (8. 1) Contraception Females Advise females of reproductive potential to use effective contraception during and for 6 months after the last dose of Methotrexate Injection therapy. Males Methotrexate can cause chromosomal damage to sperm cells. Advise males with female partners of reproductive potential to use effective contraception during and for 3 months after the last dose of Methotrexate Injection therapy. Infertility Females Based on published reports of female infertility after therapy with methotrexate, advise females of reproductive potential that Methotrexate Injection can cause impairment of fertility and menstrual dysfunction during and after cessation of therapy. It is not known if the infertility may be reversed in all affected females. Males Based on published reports of male infertility after therapy with methotrexate, advise males that Methotrexate Injection can cause oligospermia or infertility during and after cessation of therapy. It is not known if the infertility may be reversed in all affected males. The safety and effectiveness of Methotrexate Injection in pediatric patients have been established for ALL, meningeal leukemia prophylaxis and treatment, non-Hodgkin lymphoma, osteosarcoma and in pJIA. Clinical studies evaluating the use of methotrexate in pediatric patients with pJIA demonstrated safety comparable to that observed in adults with RA [see Adverse Reactions (6. 1) Risks of Serious Adverse Reactions due to Benzyl Alcohol-Preservative Due to the risk of serious adverse reactions and fatal gasping syndrome following administration of intravenous solutions containing the preservative benzyl alcohol in neonates, use only preservative-free Methotrexate Injection in neonates and low birth weight infants. The "gasping syndrome" is characterized by CNS depression, metabolic acidosis, and gasping respirations. Serious adverse reactions including fatal reactions and the "gasping syndrome" occurred in premature neonates and low birth weight infants in the neonatal intensive care unit who received drugs containing benzyl alcohol as a preservative. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0. 378 mmol/L). Additional adverse reactions include gradual neurological deterioration, seizures, intracranial hemorrhage, hematological abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol. When prescribing in infants (non-neonate, non-low birth weight), if a preservative-free formulation of Methotrexate Injection is not available and use of a benzyl alcohol-containing formulation is necessary, consider the combined daily metabolic load of benzyl alcohol from all sources including Methotrexate Injection (Methotrexate Injection contains 9. 4 mg of benzyl alcohol per mL) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known. Do not administer methotrexate formulations containing benzyl alcohol intrathecally due to the risk of severe neurotoxicity [see Warnings and Precautions (5. 3) Leukemia/Lymphoma Serious neurotoxicity, frequently manifested as generalized or focal seizures, has been reported with unexpectedly increased frequency among pediatric patients with acute lymphoblastic leukemia who were treated with intermediate-dose intravenous methotrexate (1 g/m 2 [see Warnings and Precautions (5. 8) Clinical studies of methotrexate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Methotrexate elimination is reduced in patients with renal impairment [creatinine clearance (CLcr) less than 90 mL/min, calculated using Cockcroft-Gault] [see Clinical Pharmacology (12. 3) Follow recommendations to promote methotrexate elimination and decrease risk of acute kidney injury and other methotrexate toxicities in patients who are receiving intermediate- or high-dose regimens [see Dosage and Administration (2. 2) Warnings and Precautions (5. 6) The pharmacokinetics and safety of methotrexate in patients with hepatic impairment is unknown. Patients with hepatic impairment may be at increased risk for methotrexate adverse reaction based on elimination characteristics of methotrexate [see Clinical Pharmacology (12. 3) [see Warnings and Precautions (5.

Refer to full prescribing information for drug interactions with Methotrexate Injection. ( 7 Drugs that Increase Methotrexate Exposure Coadministration of methotrexate with the following products may increase methotrexate plasma concentrations, which may increase the risk of methotrexate severe adverse reactions. Increased organ specific adverse reactions may also occur when methotrexate is coadministered with hepatotoxic or nephrotoxic products. If coadministration cannot be avoided, monitor closely for methotrexate adverse reactions when coadministered with: Nitrous Oxide Coadministration of methotrexate with nitrous oxide anesthesia potentiates the effect of methotrexate on folate-dependent metabolic pathways, which may increase the risk of severe methotrexate adverse reactions. Avoid nitrous oxide anesthesia in patients receiving methotrexate. Consider alternative therapies in patients who have received prior nitrous oxide anesthesia. Folic Acid Coadministration of methotrexate with folic acid or its derivatives decreases the clinical effectiveness of methotrexate in patients with neoplastic diseases. Methotrexate competes with reduced folates for active transport across cell membranes. Instruct patients to take folic or folinic acid only as directed by their healthcare provider [see Warnings and Precautions (5. 12) Theophylline Coadministration of methotrexate with theophylline increases theophylline plasma concentrations which may increase the risk of theophylline adverse reactions. Monitor theophylline levels and adjust the theophylline dosage in accordance with approved product labeling.

OVERDOSAGE
Manifestations Overdosage, including fatal overdosage, has occurred with methotrexate [see Warnings and Precautions (5. 19) Manifestations of overdosage include adverse reactions reported at pharmacologic doses, particularly hematologic and gastrointestinal reactions (e. , leukopenia, thrombocytopenia, anemia, pancytopenia, myelosuppression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration, or gastrointestinal bleeding). In some cases, no symptoms were reported; however, sepsis or septic shock, renal failure, and aplastic anemia were also reported. Manifestations of intrathecal overdosage include CNS symptoms (e. , headache, nausea and vomiting, seizure or convulsion, and acute toxic encephalopathy). In some cases, no symptoms were reported; however, cerebellar herniation associated with increased intracranial pressure and acute toxic encephalopathy have also been reported. Management Leucovorin and levoleucovorin are indicated to diminish the toxicity and counteract the effect of inadvertently administered overdosages of methotrexate. Administer leucovorin or levoleucovorin as soon as possible after overdosage (refer to the leucovorin or levoleucovorin prescribing information). Monitor serum methotrexate concentrations closely to guide leucovorin or levoleucovorin therapy. Monitor serum creatinine concentrations closely because high serum methotrexate concentrations may cause renal damage leading to acute renal failure. Glucarpidase is indicated for the treatment of toxic methotrexate concentrations in patients with delayed methotrexate clearance due to impaired renal function (refer to the glucarpidase prescribing information). If glucarpidase is used, do not administer leucovorin within 2 hours before or after a dose of glucarpidase because leucovorin is a substrate for glucarpidase. Hydration and urinary alkalinization may be necessary to prevent the precipitation of methotrexate and/or its metabolites in the renal tubules. Neither hemodialysis nor peritoneal dialysis has been shown to improve methotrexate elimination. However, effective clearance of methotrexate has been reported with acute, intermittent hemodialysis using a high-flux dialyzer.
NONCLINICAL TOXICOLOGY
Methotrexate has been evaluated in a number of animal studies for carcinogenic potential with inconclusive results. There is evidence that methotrexate causes chromosomal damage to animal somatic cells and human bone marrow cells [see Use in Specific Populations (8.1 8.2 8.3)
REFERENCES
1. "OSHA Hazardous Drugs." OSHA http://www.osha.gov/SLTC/hazardousdrugs/index.html

Hospira, Inc.

METHOTREXATE- methotrexate_injection, solution Product manual source documgent